Macrophage polarization is a process by which macrophage expresses different functional programs in response to microenvironmental signals. There are multiple functional states of macrophage polarization and they can be fully polarized and acquire specific phenotype like M1 (classically activated macrophages) or M2 (alternatively activated macrophages). These specific phenotypes depend on the tissue and specific microenvironment where macrophages are. On one hand macrophage polarization is very important for host defense against pathogen, but on the other hand it is essential for maintenance of homeostasis. Prolonged M1 type of macrophages is harmful for the organism and that is why tissue repair and restoration is necessary. M2 macrophages are responsible for that tissue repair, although they are also connected with chronic infectious diseases.
Classically activated macrophages were named by Mackaness in the 1960s. They express transcription factors like interferon-regulatory factor (IRF5), nuclear factor of kappa light polypeptide gene enhancer (NF-kB), activator protein 1 (AP-1) and STAT1. Typical are pro – inflammatory molecules (e.g. IFN-γ, IL-12, IL-23, TNF, IL-6, IL-1, specific chemokines and antigen presentation molecules).
M1 macrophages are irreplaceable during acute infectious diseases and provide host protection against intracellular bacteria or viruses by production of nitric oxide (NO) or reactive oxygen intermediates (ROI). IFN-γ produced by Th1 lymphocytes is the most important cytokine which is responsible for classical macrophage activation. Natural killer (NK) cells and macrophages themselves produce IFN-γ as well. This cytokine regulates gene expression programs of macrophages like cytokine receptors, cell activation markers or cell adhesion molecules. For classical macrophage activation is necessary also lipopolysaccharide (LPS) – typical for gram negative bacteria – which is mainly recognised by TLR4, or lipoteichoic acid (LTA) – typical for gram positive bacteria. Granulocyte – macrophage colony stimulation factor (GM-CSF) stimulates M1 too.
Alternatively activated macrophages cover a continuum of functional states which are divided into groups – M2a, M2b and M2c macrophages. There are different stimuli for each type – interleukin-4 (IL-4), IL-13 (M2a), immune complex + Toll-like receptor (TLR) or IL-1 receptor ligands (M2b), IL-10 and glucocorticoids (M2c).
M2a macrophages are connected with Th2 immune response. Th2 cells, eosinophils, basophils and macrophages themselves produce IL-4. They are important for encapsulation of parasites but they are also responsible for the type II hypersensitivity. For M2b is common increased IL-10 production but IL-12 production is turned off. Antigen presentation is upregulated (MHC II, CD86). M2c macrophages are important for secretion of IL-10, TGF-β. They also contribute on production of extracellular matrix components and tissue remodeling. Glucocorticoids influence their adherence, dissemination, apoptosis and phagocytosis of macrophage.
Tumour associated macrophages
Tumour-associated macrophages (TAM) are typical for their protumoural functions like promotion of cancer cell motility, metastasis formation and angiogenesis and their formation is dependent on microenvironmetal factors which are present in developing tumour. TAMs produce immunosuppressive cytokines like IL-10, TGFβ and PGE2 very small amount of NO or ROI and low levels of inflammatory cytokines (IL-12, IL-1β, TNFα, IL-6). Ability of TAMs to present tumour-associated antigens is decreased as well as stimulation of the anti-tumour functions of T and NK cells. Also TAMs are not able to lyse tumour cells. Targeting of TAM may be a novel therapeutic strategy against cancer, as has been demonstrated through the delivery of agents to either alter the recruitment and distribution of TAMs, deplete existing TAMs, or induce the re-education of TAMs from an M2 to an M1 phenotype.
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